Recent reports show that the incidence of and deaths caused by necrotizing enterocolitis (NEC) in preterm very-low-birth-weight (PVLBW) infants are on the rise. Unfortunately, NEC often rapidly progresses from early signs of intestinal inflammation to extensive necrosis within a matter of hours, making treatment and secondary prevention extremely difficult to achieve. Primary prevention should thus be the priority. Recent studies provide information that enhances our understanding of the pathophysiology and provides more practical options for the prevention of NEC. The most accepted hypothesis at present is that enteral feeding (providing substrate) in the presence of abnormal intestinal colonization by pathogens provokes an inappropriately heightened inflammatory response in immature intestinal epithelial cells of PVLBW infants. Seventy-four relevant articles were reviewed. Our focus was on the present understanding of the pathophysiology of NEC in the context of developing optimal strategies to prevent NEC in PVLBW infants. Strategies such as antenatal glucocorticoids, postnatal breast milk feeding, and cautious approach to enteral feeding failed to eliminate NEC in PVLBW infants because these strategies did not address the complexity of the pathogenesis. Probiotics seem to be the most significant advance in NEC prevention at present because of the significant range of beneficial effects at various levels of gut function and defense mechanism and the present evidence based on 19 randomized controlled trials.